Diarrheal etiology and impact of co-infections on rotavirus vaccine efficacy estimates in a clinical trial of a monovalent human-bovine (116E) oral rotavirus vaccine, Rotavac, India.

Background. Rotavirus vaccine efficacy (VE) estimates in low-resource settings are lower than in developed countries. We detected coinfections in cases of severe rotavirus diarrhea in a rotavirus VE trial to determine whether these negatively impacted rotavirus VE estimates. Methods. We performed TaqMan Array Card assays for enteropathogens on stools from rotavirus enzyme immunoassay-positive diarrhea episodes and all severe episodes (Vesikari score >= 11), from a phase 3 VE trial of Rotavac, a monovalent human-bovine (116E) rotavirus vaccine, carried out across 3 sites in India. We estimated pathogen-specific etiologies of diarrhea, described associated clinical characteristics, and estimated the impact of coinfections on rotavirus VE using a test-negative design. Results. A total of 1507 specimens from 1169 infants were tested for the presence of coinfections. Rotavirus was the leading cause of severe diarrhea even among vaccinated children, followed by adenovirus 40/41, Shigella/enteroinvasive Escherichia coli, norovirus GII, sapovirus, and Cryptosporidium species. Bacterial coinfections in rotavirus-positive diarrhea were associated with a longer duration of diarrhea and protozoal coinfections with increased odds of hospitalization. Using the test-negative design, rotavirus VE against severe rotavirus gastroenteritis increased from 49.3% to 60.6% in the absence of coinfections (difference, 11.3%; 95% confidence interval, -10.3% to 30.2%). Conclusions. While rotavirus was the dominant etiology of severe diarrhea even in vaccinated children, a broad range of other etiologies was identified. Accounting for coinfections led to an 11.3% increase in the VE estimate. Although not statistically significant, an 11.3% decrease in VE due to presence of coinfections would explain an important fraction of the low rotavirus VE in this setting.